An understanding of the molecular basis by which antigens are transported from the intestinal lumen to organized gut-associated lymphoid tissues is critical to the future development of effective mucosal vaccines. It is hypothesized that M cells provide a pathway for the uptake and delivery of IgAantigen comlexers from the intestinal lumen to naive and memory B lymphocytes situated within M cell basolateral membrane "pockets". This proposal will examine three distict steps in this pathway: adherence of IgA to M cell apical membranes, transcytosis of IgA-antigen complexes and their interaction with B cells within the pocket, and adhesion of B cells to M cell basolateral surfaces. Specific Aim A will delineate the domains of IgA involved in M cell binding and the test whether aggregation of IgA by multivalent antigens promotes endocytosis of IgA-immune complexes, and determine whether these complexes interact with B cells within the M cell pocket. Finally, Specific Aim C will define the adhesion molecules that meditate naive and memory B cell migration onto, and retention within, M cell basolateral pockets. The project will be co-sponsored by two well- established experts in the field of mucosal immunology: Dr.Marian Neutra (Children's Hospital/Harvard Medical School) and Dr. Michael Brenner (Brigham and Women's Hospital/Harvard Medical School). The Harvard Medical School community provides the technical and intellectual resources in immunology, cell biology and microbiology necessary to achieve the project's goals. The three year KO1 award will provide the applicant with-additional research training and career skills that will greatly facilitate his transition to becoming a successful independent research investigator.